Prostaglandins are twenty carbon (C20) fatty acid derivatives. Prostaglandins bind with prostaglandin receptors. These receptors, eight of which have been reported to date, are members of the superfamily of seven transmembrane domain G-coupled receptors. Prostaglandin agonists activate the receptors to which they bind, and prostaglandin antagonists inhibit the receptors to which they bind; thereby producing biological effects.
For example, four receptors couple to an increase in intracellular cAMP, and are smooth muscle relaxants. EP4, DP, IP (prostacyclin) and EP2 are in this category. Three receptors couple to an increase in intracellular calcium and contract smooth muscle: the EP1 (see Funk C D, Furci L, Fitzgerald G A, Cloning and expression of a cDNA for the human prostaglandin receptor EP1 subtype. J. Biol. Chem. 1995 270, 18910–18916), the FP (ligand: PGF2α) (see Abramovitz M, Boie Y, Mguyen T, Rushmore T H, Bayne M A, Metters K M, Slipetz D M and Grygorczyk R Cloning and expression of a cDNA for the human prostanoid FP receptor. J. Biol. Chem 1994 269 2632–2636), and the TP (thromboxane) receptors. Finally, the EP3 receptor couples to a lowering of intracellular cAMP, and thus prevents relaxation of smooth muscle. Activation of this receptor blocks the forskolin-induced increase in intracellular cAMP. In addition to the gene products, alternate splicing gives rise to multiple isoforms of the EP3 (eight isoforms) (see Ichikawa E A Molecular aspects of the structures and functions of the prostaglandin E receptors J. Lipid Med. Cell Signal. 1996 14 83–87) and the TP (two isoforms) (see Krauss A H P, Woodward D F, Gibson L L, Protzman C E, Williams L S, Burk R M, Gac T S, Roof M B, Abbas F, Marshall K, Senior J Evidence for human thromboxane receptor heterogeneity using a novel series of 9,11-cyclic carbonate derivatives of prostaglandin-F2-alpha Br. J. Pharm. 1996 117(6) 1171–1180). These isoforms alter the carboxy-terminal region and thus the coupling of the G-proteins, rather than the prostaglandin binding regions. Pharmacological studies have provided evidence for the existence of other subtypes of receptors (see Corsini A. Folco G C, Fumagalli R. (5Z)-Carbacyclin discriminates between prostacyclin receptors coupled to adenylate cyclase in vascular smooth muscle and platelets. Br. J. Pharmacol. 1987 90, 255–261) or splice variants. The evidence is particularly compelling for the DP receptor and an FP or EP1 variant (Id., and see Woodward D F, Gil D W, Chen J, Burk R M, Kedzie, K M, Krauss, A H-P, Emerging evidence for additional prostanoid receptor subtypes Cur. Top. Pharmacol. 1998 4, 153–162, and Woodward D F, Madhu C, Rix P, Kharlamb A Studies on the ocular effects of a pharmacologically novel agent prostaglandin F2 alpha 1-OCH3 N-S Arch. Pharm., 1998. 358, (1). P1713–P1713). In addition, negative regulatory proteins (see Orlicky, D J Negative regulatory activity of a prostaglandin F2a receptor associated protein (FPRP) Prostaglandins, Leukotr. Ess. Fatty Acids 1996 54(5) 247–259; and Jakobsson P J, Morgenstern R, Mancini J, FordHutchinson A, Persson B Membrane-associated proteins in ecosanoid and glutathione metabolism (MAPEG)-A widespread protein superfamily Am. J. Resp. Crit. Care Med. 2000 161, S20–S24) and active transport proteins have recently been identified.
The receptors' nomenclature describes the naturally occurring prostaglandin to which they have the highest affinity, e.g., the EP series of receptors have the highest affinity for the ligand PGE2 (see Coleman R A, Smith, W L, Narumia S Classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol. Rev. 1994 46, 205–229). However, all the naturally-occurring prostaglandins have some affinity for all eight of the receptors (see Kiriyama M, Ushikubi F, Kobayashi T, Hirata M, Sugimoto Y, Narumiya S Binding specificities of the prostanoid receptors. Br. J. Pharmacol. 1997 122 217–224).
Naturally-occurring prostaglandins include PGE1 and PGE2, PGF2α, prostacyclin (PGI), thromboxane and PGD2. Naturally occurring prostaglandins have substituent groups at the C9 and C11 positions on the cyclopentyl ring, a cis double bond between C5 and C6, and a trans double bond between C13 and C14. Thus, the naturally occurring prostaglandins are exemplified by the following structures.

All naturally occurring prostaglandins have a carboxylic acid moiety at the C1 position. The carboxylic acid moiety is a site for metabolic degradation by beta oxidation, which contributes to the rapid metabolism of the naturally occurring prostaglandins. Attempts have been made to prevent beta oxidation by modifying the carboxylic acid moiety at the 1 position as an ester moiety, a sulfonamide moiety, and as a tetrazole (see PCT Publication Nos. WO 99/12895, WO 99/12896, and WO 99/12898). However, such modifications have either resulted in only modest increases in half-life (such as the esters) or resulted in compounds with diminished potency.
An alternative approach has been to replace C1 with a heteroatom. For example, PGF analogs containing a sulfonic acid moiety at C1 (see Iguchi, Y.; Kori, S.; Hayashi, The chemistry of prostaglandins containing the sulfo group. M. J. Org. Chem., 1975 40, 521–523) and PGF analogs containing a phosphonic acid moiety at C1 (see Kluender, H. C. & Woessner, W., The Synthesis of dimethylphosphonoprostaglandin analogs, Prostaglandins and Medicine, 1979 2: pp. 441–444,) have been disclosed. However, such compounds suffer from significantly diminished potency.
Further research in the area of heteroatom-containing C1 replacements has been hampered by the lack of a general synthetic route to advanced or key intermediates that would allow for the rapid preparation of a multitude of variants to replace C1. The Corey route to prostaglandins was specifically designed for a carboxcyclic acid moiety, and modifications which create reagents with relatively acidic protons are either incompatible with this route or cause significant optimization of this difficult step for each new C1 replacement. Syntheses of Prostaglandin analogs via the Corey route are described in the following references: Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W J. Am. Chem. Soc., 1969, 91, 5675 and Corey. E. J.; Schaaf, T. K.; Huber, W; Koelliker, U.; Weinshenker, N. M.; J. Am. Chem. Soc., 1970, 92, 397.
Thus, while a few prostaglandin analogs wherein C1 has been replaced with a heteroatom-containing moiety have been disclosed, there is a continuing need for suitable C1 replacements that result in potent, selective prostaglandin derivatives for the treatment of a variety of diseases and other conditions. Therefore, it is an object of this invention to provide 2-decarboxy-2-phosphinico derivatives of prostaglandins that can be used to treat medical and cosmetic conditions.
Prostaglandin analogs have potent biological activities of a hormonal or regulatory nature. Examples of the biological activities and the conditions they can be used to treat are discussed below.